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Thromb Haemost 2002; 87(06): 1026-1033
DOI: 10.1055/s-0037-1613128
Review Article
Schattauer GmbH

Selective Inhibition of Protease-activated Receptor 4-dependent Platelet Activation by YD-3

Chin-Chung Wu
2   Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung
,
Tsong-Long Hwang
3   Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan
,
Chang-Hui Liao
3   Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan
,
Sheng-Chu Kuo
4   Graduate Institute of Pharmaceutical Chemistry, China Medical College, Taichung
,
Fang-Yu Lee
5   Yung-Shin Pharmaceutical Industry Co. Ltd, Taichung, Taiwan
,
Chun-Yann Lee
4   Graduate Institute of Pharmaceutical Chemistry, China Medical College, Taichung
,
Che-Ming Teng
1   Pharmacological Institute, College of Medicine, National Taiwan University, Taipei
› Author Affiliations
Further Information

Publication History

Received 05 November 2001

Accepted after resubmission 22 February 2002

Publication Date:
08 December 2017 (online)

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Summary

In the present study, the antiplatelet effect and its mechanism of a new synthetic compound YD-3 [1-benzyl-3-(ethoxycarbonylphenyl)-indazole] were examined. YD-3 inhibited the aggregation of washed human platelets caused by protease-activated receptor (PAR) 4 agonist peptide GYPGKF (IC50 = 0.13 ± 0.02 µM), but had no or little effect on that by thrombin, PAR1 agonist peptide SFLLRN, collagen or U46619. YD-3 produced a parallel, rightward shift of the concentration-response curve for GYPGKF without decreasing of the maximum platelet aggregation, indicating a competitive antagonism. In contrast to human platelets, both thrombin- and GYPGKF-induced mouse platelet shape change and aggregation were completely inhibited by YD-3. YD-3 also selectively prevented GYPGKF-induced intracellular Ca2+ mobilization in human platelets. Furthermore, in the PAR1-desensitized human platelets, thrombin induced a relatively slow rise and decay of calcium mobilization that was significantly inhibited by YD-3. In addition, the synergistic effect of SFLLRN and GYPGKF on platelet activation was prevented by YD-3. YD-3 also inhibits both fMLP-stimulated neutrophil- and purified cathepsin G-induced platelet aggregation, which has been demonstrated to be PAR4-dependent. Taken together, our results suggest that YD-3 selectively inhibits PAR4-dependent platelet activation through blockade of PAR4. To the best of our knowledge, it is the first non-peptide PAR4 antagonist.

Keywords

Protease-activated receptor - platelet activation - YD-3
 

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